Phenethanolamine derivatives

Abstract

The invention is directed to phenethanolamine derivatives and their pharmaceutically compatible salts, having the formula <IMAGE> I wherein n is the number 1 or 2; L1 and L2 are hydrogen, C1-3-(alkyl)carbonyl or C1-3(alkoxy) carbonyl; T is hydrogen or methyl; X1 and X2 are phenyl or phenyl which is monosubstituted in the m-position by Br, Cl, F, CF3 and NO2; Y is -(CH2)1-6-O-G, -(CH2)1-6-CH=CH-C(O)-Z, -C(O)-Z or -CH(COOR'')2; G is C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl or -(CH2)1-4-Q; Q is phenoxy, phenyl, p-fluorophenyl or p-phenoxyphenyl; Z is a -OR or -N(R,R'); R and R' are hydrogen or C1-4-alkyl or R and R' together with the N-atom to which they are attached form a 5- or 6-membered saturated ring which optionally contains an O-atom or an additional N-atom; and R'' is C1-4-alkyl. The compounds of the invention have catabolic activity and can be used for the treatment of obesity and of diabetes mellitus or of conditions which are associated with an increased protein breakdown, or as feed additives for fattening animals.

We claim: 
     
       1. A compound of the formula: ##STR6## wherein n is the number 1 or 2; L 1  and L 2  are hydrogen, C 1-3  -(alkyl)carbonyl or C 1-3  (alkoxy)carbonyl; T is hydrogen or methyl; X 1  and X 2  are phenyl or phenyl which is monosubstituted in the m-position by Br, Cl, F, CF 3  or NO 2  : Y is --(CH 2 ) 1-6  --O--G, --(CH 2 ) 1-6  --CH═CH--C(O)--Z, --C(O)--Z or --CH(COOR") 2  ; G is C 1-4  -alkyl, C 1-4  -alkoxy-C 1-4  -alkyl or --(CH 2 ) 1-4  --Q; Q is phenoxy, phenyl, p-fluorophenyl or p-phenoxyphenyl; Z is a -OR or -N(R,R'); R and R' are hydrogen or C 1-4  -alkyl or R and R' together with the N-atom to which they are attached form a 5- or 6-membered saturated ring which optionally contains an O-atom or an additional N-atom; and R" is C 1-4  -alkyl; as well as the physiologically compatible salts thereof. 
     
     
       2. A compound according to claim 1, in which G is C 1-4  -alkoxyalkyl. 
     
     
       3. A compound according to claim 2, in which n is the number 1. 
     
     
       4. A compound according to claim 3, in which L 1  and L 2  are acetyl, ethoxycarbonyl or hydrogen. 
     
     
       5. A compound according to claim 4 wherein L 1  and L 2  are hydrogen. 
     
     
       6. A compound according to claim 4, in which T is methyl. 
     
     
       7. A compound according to claim 6, in which the C-atom to which the methyl group T is attached has the R-configuration. 
     
     
       8. A compound according to claim 6 in which X 1  and X 2  are phenyl, m-fluorophenyl or m-chlorophenyl. 
     
     
       9. A compound according to claim 8 in which the C-atom to which X 1  is attached has the R-configuration and the C-atom to which X 2  is attached has the R- or S-configuration. 
     
     
       10. A compound according to claim 9 wherein X 1  and X 2  are m-chlorophenyl. 
     
     
       11. A compound according to claim 8, in which Y is 2-methoxyethoxyethyl, 2-p-fluorophenethoxyethyl, 2-phenoxyethoxyathyl, p-phenoxybenzyloxyethyl, dimethylcarbamoyl, methoxycarbonylallyl, bis(methoxycarbonyl)-methyl, ethoxycarbonyl, 2-phenethoxyethyl or 2-ethoxyethyl. 
     
     
       12. A compound according to claim 11, wherein Y is 2-phenethoxyethyl or 2-ethoxyethyl. 
     
     
       13. A compound according to claim 1, in which n is the number 1; L 1  and L 2  are hydrogen; T is hydrogen or methyl; X 1  and X 2  are m-chlorophenyl and Y is 2-phenethoxyethyl or 2-ethoxy-ethyl, wherein the C-atom to which X 1  is attached has the R-configuration and the C-atom to which X 2  is attached has the R- or S-configuration. 
     
     
       14. A compound according to claim 1, which is α,α'-[[[p-(2-Ethoxyethoxy)phenethyl]imino]dimethylene]bis[(R)-m-chlorobenzyl alcohol]. 
     
     
       15. A compound according to claim 1 selected from the group consisting of: α,α'-[[[(R)-α-Methyl-p-[2-(phenethoxy)ethoxy]phenethyl]imino]dimethylene]bis[(R)-m-chlorobenzyl alcohol],   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl]-(R)-α-methyl-p-[2-(phenethoxy)ethoxy]phenethyl]amino]methyl]benzyl alcohol,   3-chloro-α,α'-[[[(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]imino]dimethylene]di-(R)-benzyl alcohol,   (S)-m-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methylphenethyl][(R)-β-hydroxyphenethyl]amino]methyl]-benzyl alcohol,   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl][p-(2-ethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol and   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl][p-(2-phenethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol.   
     
     
       16. A pharmaceutical composition comprising a physiologically active compounde and a compatible pharmaceutical carrier, wherein said active compound has the formula ##STR7## wherein n is the number 1 or 2; L 1  and L 2  are hydrogen C 1-3  -(alkyl) carbonyl or C 1-3  (alkoxy)carbonyl; T is hydrogen or methyl; X 1  and X 2  are phenyl or phenyl which is monosubstituted in the m-position by Br Cl, F, CF 3  or NO 2  ; Y is --(CH 2 ) 1-6  --O--G, --(CH 2 ) 1-6  --CH═CH--C(O)--Z, --C(O)--Z or --CH(COOR") 2  ; G is C 1-4  -alkyl, C 1-4  -alkoxy-C 1-4  -alkyl or --(CH 2 ) 1-4  --Q; Q is phenoxy, phenyl, p-fluorophenyl or p-phenoxyphenyl; Z is a group OR or N(R,R'); and R' are hydrogen or C 1-4  alkyl, or R and R' together with the N-atom to which they are attached form a 5- or 6-membered saturated ring which optionally contains an O-atom or an additional N-atom; R" is C 1-4  -alkyl, as well as physiologically compatible salts thereof. 
     
     
       17. A composition according to claim 16, in which n is the number 1. 
     
     
       18. A composition according to claim 17, in which L 1  and L 2  are acetyl, ethoxycarbonyl or hydrogen. 
     
     
       19. A composition according to claim 18, wherein L 1  and L 2  are hydrogen. 
     
     
       20. A composition according to claim 18, in which T is methyl. 
     
     
       21. A composition according to claim 20, wherein the C-atom to which the methyl group T is attached has the R-configuration. 
     
     
       22. A composition according to claim 20, in which X 1  and X 2  are phenyl, m-fluorophenyl or m-chlorophenyl. 
     
     
       23. A composition according to claim 22, in which the c-atom to which X 1  is attached has the R-configuration and the C-atom to which X 2  is attached has the R- or S-configuration. 
     
     
       24. A composition according to claim 23, wherein X 1  and X 2  are m-chloro-phenyl. 
     
     
       25. A compound according to claim 22 wherein T is methyl and wherein the C-atom to which T is attached has the R-configuration and wherein the C-atom to which X 1  is attached has the R-configuration. 
     
     
       26. A composition according to claim 26, in which Y is 2-methoxyethoxyethyl, 2-p-fluorophenethoxyethyl, 2-phenoxyethoxyethyl, p-phenoxybenzyloxyethyl, dimethylcarbamoyl, methoxycarbonylallyl, bis(methoxycarbonyl)-methyl, ethoxycarbonyl or especially 2-phenethoxyethyl or 2-ethoxyethyl. 
     
     
       27. A composition according to claim 16, wherein n is the number 1; L 1  and L 2  are hydrogen; T is hydrogen or methyl; X 1  and X 2  are m-chlorophenyl; Y is 2-phenethoxyethyl or 2-ethoxyethyl: wherein the C-atom to which X 1  is attached has the R-configuration and the C-atom to which X 2  is attached has the R- or S-configuration. 
     
     
       28. A composition according to claim 16 wherein said active compound is α,α'-[[[p-(2-Ethoxyethoxy)phenethyl]imino]-dimethylene]bis[(R)-m-chlorobenzyl alcohol]. 
     
     
       29. A composition according to claim 16, wherein said active compound is selected from the group consisting of; α,α'-[[[(R)-α-Methyl-p-[2-(phenethoxy)ethoxy]-phenethyl]imino]dimethylene]bis[(R)-m-chlorobenzyl alcohol],   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl](R)-α-methyl-p-[2-(phenethoxy)ethoxy]phenethyl]amino]methyl]benzyl alcohol,   3-chloro-α,α'-[[[(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]imino]dimethylene]di-(R)-benzyl alcohol,   (S)-m-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methylphenethyl][(R)-β-hydroxyphenthyl]amino]methyl]-benzyl alcohol,   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl][p-(2-ethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol and   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl][p-(2-phenethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol.   
     
     
       30. A composition according to claim 16, wherein said carrier is a solid material. 
     
     
       31. A composition according to claim 16 wherein said carrier is an aqueous liquid or oily material. 
     
     
       32. A method for treating a subject suffering from obese adult diabetes, which method comprises administering to said subject a therapeutically effective amount a compound of the formula ##STR8## wherein n is the number 1 or 2; L 1  and L 2  are hydrogen, C 1-3  -(alkyl)carbonyl or C 1-3  (alkoxy)carbonyl; T is hydrogen or methyl; X 1  and X 2  are phenyl or phenyl which is monosubstituted in the m-position by Br, Cl, F, CF 3  or NO 2  ; Y is --(CH 2 ) 1-6  --O--G, --(CH 2 ) 1-6  --CH═CH--C(O)--Z, --C(O)--Z or --CH(COOR") 2  ; G is C 1-4  -alkyl, C 1-4  -alkoxy-C 1-4  -alkyl or --(CH 2 ) 1-4  --Q; Q is phenoxy, phenyl, p-fluorophenyl or p-phenoxyphenyl; Z is a -OR or -N(R,R'): R and R' are hydrogen or C 1-4  -alkyl or R and R' together with the N-atom to which they are attached form a 5- or 6-membered saturated ring which optionally contains an O-atom or an additional N-atom: and R" is C 1-4  -alkyl; as well as the physiologically compatible salts thereof. 
     
     
       33. A method according to claim 32 wherein said compound is selected from the group consisting of α,α'-[[[(R)-α-Methyl-p-[2-(phenethoxy)ethoxy]phenethyl]imino]dimethylene]bis[(R)-m-chlorobenzyl alcohol],   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl]-(R)-α-methyl-p-[2-(phenethoxy)ethoxy]phenethyl]amino]methyl]benzyl alcohol,   3-chloro-α,α'-[[[(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]imino]dimethylene]di-(R)-benzyl alcohol,   (S)-m-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methylphenethyl][(R)-β-hydroxyphenethyl]amino]methyl]-benzyl alcohol,   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl][p-(2-ethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol and   (R)-m-chloro-α-[[[(S)-m-chloro-β-hydroxyphenethyl][p-(2-phenethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol, and   α,α'-[[[p-(2-Ethoxyethoxy)phenethyl]imino]-dimethylene]bis[(R)-m-chlorobenzyl alcohol].   
     
     
       34. A method according to claim 32, wherein said compound is α,α'-[[p-(2-Ethoxyethoxy)phenethyl]imino]-dimethylene]bis[(R)-m-chlorobenzyl alcohol].